tbuckley/cabot-search huggingface dataset:
Improved sensitivity in identification of first recurrences of metastatic breast cancer with a combination of cell and cell-free liquid biopsy analysis.
Authors: Giuseppe Di Caro, David Bourdon, Jiyun Byun, Tatjana Singer, Amanda Anderson, Martin Blankfard, Alisa Tubbs, Rick Wenstrup
Journal: Journal of Clinical Oncology (2022)

e13003 Background: Liquid biopsy analysis detecting circulating tumor cells (CTC) or circulating tumor DNA (ctDNA) is a non-invasive approach that may provide clinically actionable information for patients’ (pts) treatment decisions when conventional biopsy is otherwise inaccessible or infeasible. Here we report a liquid biopsy method including CTC characterization &amp; ctDNA alterations in pts symptomatic of first metastatic recurrence with a history of primary breast cancer (BC). Methods: Blood samples from 34 symptomatic BC pts were collected for cell &amp; cell-free DNA analysis before undergoing contemporaneous tissue biopsy &amp; initiating treatment for metastatic BC (MBC). Blood was also collected from 25 blood donors (HD) with no known cancer history. After plasma isolation, nucleated cells were plated, &amp; slides were bio-banked. Immunofluorescent staining &amp; subsequent imaging were performed on replicate slides. CTCs were identified using Epic Sciences digital imaging &amp; machine learning algorithms trained to identify breast cancer cells. Single-cell (sc) isolation for genomic quantification of large-scale transitions (scLST) was used to further characterize individual CTCs. cfDNA from bio-banked plasma was analyzed to detect Class IA alterations in ctDNA. Results: Within this cohort of 34 patients, CTCs &amp; ctDNA alterations were detected in 80% &amp; 58%, respectively while no CTCs &amp; ctDNA were detected in the HD cohort suggesting high specificity (100% &amp; 100%). In this study, 26 pts were confirmed MBC (M1-BC) by tissue biopsy, 3 pts were non-MBC by tissue biopsy but still diagnosed as metastatic (Mx-BC), &amp; 5 pts were confirmed non-MBC (M0-BC). To benchmark the cellular (CTCs &amp; scLST+CTCs) &amp; genomic (ctDNA) individual platforms, we designed thresholds of CTCs &gt; 4, scLST+CTC+, &amp; ctDNA+ that optimally identified M1-BC pts with high specificity (100%, 100%, &amp; 100%) but low sensitivity (46%, 46%, &amp; 50%). CTCs &gt; 4 &amp; scLST+CTC+ cutoffs had low concordance with the presence of ctDNA alterations, suggesting these platforms provide independent &amp; complementary value when identifying MBC. To test this hypothesis, we designed combination models [CTC &gt; 4][ctDNA+] &amp; [scLST+CTC+][ctDNA+] that significantly improved sensitivity (75% &amp; 67%) over individual platforms while maintaining high specificity (100% &amp; 100%) when identifying the first recurrence of metastasis in BC pts. Conclusions: To our knowledge, this is the first report showing the additive &amp; complementary value of models combining cellular &amp; genomic liquid biopsy platforms for the detection of the first MBC recurrence. Our data suggest the clinical utility of combined CTC &amp; ctDNA platforms for the identification of MBC when tissue biopsy is inaccessible or infeasible.
Accuracy and Efficiency of Machine Learning–Assisted Risk-of-Bias Assessments in “Real-World” Systematic Reviews
Authors: Anneliese Arno, James Thomas, Byron Wallace, Iain J. Marshall, Joanne E. McKenzie, Julian H. Elliott
Journal: Annals of Internal Medicine (2022)

Background: Automation is a proposed solution for the increasing difficulty of maintaining up-to-date, high-quality health evidence. Evidence assessing the effectiveness of semiautomated data synthesis, such as risk-of-bias (RoB) assessments, is lacking. Objective: To determine whether RobotReviewer-assisted RoB assessments are noninferior in accuracy and efficiency to assessments conducted with human effort only. Design: Two-group, parallel, noninferiority, randomized trial. (Monash Research Office Project 11256) Setting: Health-focused systematic reviews using Covidence. Participants: Systematic reviewers, who had not previously used RobotReviewer, completing Cochrane RoB assessments between February 2018 and May 2020. Intervention: In the intervention group, reviewers received an RoB form prepopulated by RobotReviewer; in the comparison group, reviewers received a blank form. Studies were assigned in a 1:1 ratio via simple randomization to receive RobotReviewer assistance for either Reviewer 1 or Reviewer 2. Participants were blinded to study allocation before starting work on each RoB form. Measurements: Co-primary outcomes were the accuracy of individual reviewer RoB assessments and the person-time required to complete individual assessments. Domain-level RoB accuracy was a secondary outcome. Results: Of the 15 recruited review teams, 7 completed the trial (145 included studies). Integration of RobotReviewer resulted in noninferior overall RoB assessment accuracy (risk difference, −0.014 [95% CI, −0.093 to 0.065]; intervention group: 88.8% accurate assessments; control group: 90.2% accurate assessments). Data were inconclusive for the person-time outcome (RobotReviewer saved 1.40 minutes [CI, −5.20 to 2.41 minutes]). Limitation: Variability in user behavior and a limited number of assessable reviews led to an imprecise estimate of the time outcome. Conclusion: In health-related systematic reviews, RoB assessments conducted with RobotReviewer assistance are noninferior in accuracy to those conducted without RobotReviewer assistance. Primary Funding Source: University College London and Monash University.
Comparative effectiveness of systemic treatments in desmoid tumors.
Authors: Philippos Apolinario Costa, Arshia Arora, Heng Tan, Yanelys Fernandez, Leticia Campoverde, Priscila Barreto Coelho, Steven Bialick, Andrea P. Espejo-Freire, Emily Jonczak, Gina Z. D'Amato, Ty Subhawong, Jonathan C. Trent
Journal: Journal of Clinical Oncology (2022)

e23534 Background: Many systemic treatment options are described for desmoid tumors, including hormonal therapies, non-steroidal anti-inflammatory drugs, cytotoxic chemotherapeutic agents, and most recently, tyrosine kinase inhibitors. Although many options are described, randomized data is scarce. The lack of comparative studies precludes a definitive sequence of the existing systemic treatments in the management of desmoid tumors. Here we retrospectively compare sorafenib with cytotoxic chemotherapy to generate objective data to guide treatment choice. Methods: We analyzed all patients with desmoid tumors treated with doxorubicin, dacarbazine, vinblastine, vinorelbine, methotrexate, or sorafenib in the first-line setting at a single center from 2000-2021. The primary endpoint was investigator-assessed progression-free survival. The secondary endpoint was the rate of toxic effects recorded accordingly to the Common Terminology Criteria for Adverse Events. We calculated progression-free survival (PFS) using the Kaplan-Meier method with Log-Rank Test to estimate the 95% confidence interval. Results: 79 patients ultimately received systemic therapies. Median follow-up was 5.6 years (0 to 7.9), 69% were women, and median age at diagnosis was 37 (range 5-77). Regarding race and ethnicity, 74% were White, 26%, Black and 45%, Latino. The tumor was in the lower extremity in 21 (27%) cases, trunk in 18 (23%) cases, abdominal wall in 13 (16%), intra-abdomen in 9 (11%), upper extremity in 7 (9%), head-neck in 7 (9%) and breast in 4 (5%). Surgery before systemic treatment was used in 20 (25%) patients. The regiments used were sorafenib (n = 32), doxorubicin with dacarbazine (n = 13), liposomal doxorubicin (n = 11), methotrexate with vinblastine (n = 11), methotrexate with vinorelbine (n = 8) and methotrexate monotherapy (n = 1). The 2-year progression-free survival rate was 80% (95% confidence interval [CI], 0.64 to 0.96) in the cytotoxic chemotherapy group and 66% (95% CI, 0.46 to 0.86) in the sorafenib group (P = 0.06). The most frequently reported adverse events on the cytotoxic group were grade 1 or 2 events of nausea (25%) and rash (15%), and on sorafenib were grade 1 or 2 events of palmar-plantar erythrodysesthesia (40%) and fatigue (25%). There were no treatment-related deaths reported. Conclusions: There was no statistical difference between the analyzed treatments, although there was a trend toward lower progression rates with cytotoxic therapy.
Patient-reported outcome measures and surgical retreatment rates from 181 patients treated with water vapor thermal therapy (Rezūm™)
Authors: M.J. Connor, A. Rai, C. Khoo, E.J. Bass, D. Eldred-Evans, S. Agarwal, M. Winkler, H. Abboudi, R. Dasgupta, T. El-Husseiny, H.U. Ahmed
Journal: European Urology (2022)
Cellular and Engineered Organoids for Cardiovascular Models
Authors: Dilip Thomas, Suji Choi, Christina Alamana, Kevin Kit Parker, Joseph C. Wu
Journal: Circulation Research (2022)

An ensemble of in vitro cardiac tissue models has been developed over the past several decades to aid our understanding of complex cardiovascular disorders using a reductionist approach. These approaches often rely on recapitulating single or multiple clinically relevant end points in a dish indicative of the cardiac pathophysiology. The possibility to generate disease-relevant and patient-specific human induced pluripotent stem cells has further leveraged the utility of the cardiac models as screening tools at a large scale. To elucidate biological mechanisms in the cardiac models, it is critical to integrate physiological cues in form of biochemical, biophysical, and electromechanical stimuli to achieve desired tissue-like maturity for a robust phenotyping. Here, we review the latest advances in the directed stem cell differentiation approaches to derive a wide gamut of cardiovascular cell types, to allow customization in cardiac model systems, and to study diseased states in multiple cell types. We also highlight the recent progress in the development of several cardiovascular models, such as cardiac organoids, microtissues, engineered heart tissues, and microphysiological systems. We further expand our discussion on defining the context of use for the selection of currently available cardiac tissue models. Last, we discuss the limitations and challenges with the current state-of-the-art cardiac models and highlight future directions.
A comprehensive profiling of the immune microenvironment of breast cancer brain metastases
Authors: Gaia Griguolo, Anna Tosi, Maria Vittoria Dieci, Susan Fineberg, Valentina Rossi, Annavera Ventura, Michele Bottosso, Luc Bauchet, Federica Miglietta, Jack Jacob, Valerie Rigau, Matteo Fassan, William Jacot, PierFranco Conte, Antonio Rosato, Amelie Darlix, Valentina Guarneri
Journal: Neuro-Oncology (2022)

Despite potential clinical implications, the complexity of breast cancer (BC) brain metastases (BM) immune microenvironment is poorly understood. Through multiplex immunofluorescence, we here describe the main features of BCBM immune microenvironment (density and spatial distribution) and evaluate its prognostic impact.Sixty BCBM from patients undergoing neurosurgery at three institutions (2003-2018) were comprehensively assessed using two multiplex immunofluorescence panels (CD4, CD8, Granzyme B, FoxP3, CD68, pan-cytokeratin, DAPI; CD3, PD-1, PD-L1, LAG-3, TIM-3, CD163, pan-cytokeratin, DAPI). The prognostic impact of immune subpopulations and cell-to-cell spatial interactions was evaluated.Subtype-related differences in BCBM immune microenvironment and its prognostic impact were observed. While in HR-/HER2- BM and HER2+ BM, higher densities of intra-tumoral CD8+ lymphocytes were associated with significantly longer OS (HR 0.16 and 0.20, respectively), in HR+/HER2- BCBMs a higher CD4+FoxP3+/CD8+ cell ratio in the stroma was associated with worse OS (HR 5.4). Moreover, a higher density of intra-tumoral CD163+ M2-polarized microglia/macrophages in BCBMs was significantly associated with worse OS in HR-/HER2- and HR+/HER2- BCBMs (HR 6.56 and 4.68, respectively), but not in HER2+ BCBMs. In HER2+ BCBMs, multiplex immunofluorescence highlighted a negative prognostic role of PD-1/PD-L1 interaction: patients with a higher percentage of PD-L1+ cells spatially interacting with (within a 20 µm radius) PD-1+ cells presented a significantly worse OS (HR 4.60).Our results highlight subtype-related differences in BCBM immune microenvironment and identify two potential therapeutic targets, M2 microglia/macrophage polarization in HER2- and PD-1/PD-L1 interaction in HER2+ BCBMs, which warrant future exploration in clinical trials.
Safety and tolerability of long-term treatment with darolutamide in patients with metastatic castration-resistant prostate cancer
Authors: E. Vjaters, K. Fizazi, N.D. James, T.L. Tammela, N. Matsubara, F. Priou, P. Beuzeboc, T. Lesimple, P. Bono, V. Kataja, J.A. Garcia, A. Protheroe, J. Aspegren, H. Joensuu, I. Kuss, S. Thiele, S. Fiala-Buskies, R.H. Jones
Journal: European Urology (2022)
Cohort study of oligorecurrent prostate cancer patients: Oncological outcomes of patients treated with salvage lymph node dissection via PSMA radioguided surgery
Authors: S. Knipper, M. Mehdi Irai, R. Simon, D. Köhler, R. Isabel, M. Eiber, F.W.B. Van Leeuwen, P. Van Leeuwen, L. Budäus, T. Steuber, M. Graefen, P. Tennstedt, M. Heck, T. Horn, T. Maurer
Journal: European Urology (2022)
Animal Models of Atherosclerosis–Supportive Notes and Tricks of the Trade
Authors: Anton Gisterå, Daniel F.J. Ketelhuth, Stephen G. Malin, Göran K. Hansson
Journal: Circulation Research (2022)

Atherosclerotic cardiovascular disease is a major cause of death among humans. Animal models have shown that cholesterol and inflammation are causatively involved in the disease process. Apolipoprotein B-containing lipoproteins elicit immune reactions and instigate inflammation in the vessel wall. Still, a treatment that is specific to vascular inflammation is lacking, which motivates continued in vivo investigations of the immune-vascular interactions that drive the disease. In this review, we distill old notions with emerging concepts into a contemporary understanding of vascular disease models. Pros and cons of different models are listed and the complex integrative interplay between cholesterol homeostasis, immune activation, and adaptations of the vascular system is discussed. Key limitations with atherosclerosis models are highlighted, and we suggest improvements that could accelerate progress in the field. However, excessively rigid experimental guidelines or limiting usage to certain animal models can be counterproductive. Continued work in improved models, as well as the development of new models, should be of great value in research and could aid the development of cardiovascular disease diagnostics and therapeutics of the future.
Multiparametric analysis in GBM plasma extracellular vesicles (Evs) and surface marker expression profile.
Authors: Abudumijiti(Zack) Aibaidula, Cori E. Fain, Luz Cumba Garcia, Miyeon Jung, Aaron J. Johnson, Ian F. Parney
Journal: Journal of Clinical Oncology (2022)

2038 Background: Glioblastoma (GBM) is the most common malignant brain tumor with poor clinical prognosis. Management of GBM is hampered by the lack of an accurate test that can be used for differential diagnosis of tumor progression from inflammatory pseudoprogression. Plasma extracellular vesicles (EVs) has been shown to be a promising source for biomarker identification. In this project, we aimed to identify GBM plasma EV markers that could serve as the basis of a liquid biopsy. Methods: Sample preparation, assay controls and instrument calibration were performed following MIFlowCyt-EV guideline. Plasma samples were subjected to 2-step centrifugations to remove cell debris and platelets. 10ul of plasma sample was diluted with 90ul filtered PBS, then stained for EV surface markers including CD9, CD31, CD45, CD41a and CD11b, as well as actin phalloidin. Stained plasma samples were purified using IZON qEV1/70nm column, then EV fractions were analyzed using full spectrum Cytek Aurora flow cytometer. Clustering analysis was performed on EV events (CD9 +/ actin phalloidin -) using t-SNE and FlowSOM extensions from FlowJo plugins. Results: Compared to normal donors, GBM plasma EVs were bigger in size (higher SSC value) and expressed higher levels of CD9, CD31, CD45 and CD11b while ND plasma EVs had higher CD41a expression. t-SNE and FlowSOM analysis demonstrated that GBM plasma EVs had a unique surface marker expression profile compared to ND EVs. It also showed 10 EV sub-populations that differed in size as well as various surface marker expression levels. Four of these subpopulations were enriched in GBM EVs, while three of these were enriched in ND EVs. Conclusions: This multiparametric analysis revealed that GBM plasma EVs had a unique surface marker expression profile compared to ND plasma EVs. Further separation and molecular profiling analysis based on each sub population could reveal EV biomarkers that are unique to each sample population.
Clinical outcomes in patients with relapsed/refractory FLT3-mutated acute myeloid leukemia treated with gilteritinib who received prior midostaurin or sorafenib
Authors: Alexander E. Perl, Naoko Hosono, Pau Montesinos, Nikolai Podoltsev, Giovanni Martinelli, Nicki Panoskaltsis, Christian Recher, Catherine C. Smith, Mark J. Levis, Stephen Strickland, Christoph Röllig, Marco Groß-Langenhoff, Wen-Chien Chou, Je-Hwan Lee, Hisayuki Yokoyama, Nahla Hasabou, Qiaoyang Lu, Ramon V. Tiu, Jessica K. Altman
Journal: Blood Cancer Journal (2022)

The fms-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib is indicated for relapsed or refractory (R/R) FLT3-mutated acute myeloid leukemia (AML), based on its observed superior response and survival outcomes compared with salvage chemotherapy (SC). Frontline use of FLT3 tyrosine kinase inhibitors (TKIs) midostaurin and sorafenib may contribute to cross-resistance to single-agent gilteritinib in the R/R AML setting but has not been well characterized. To clarify the potential clinical impact of prior TKI use, we retrospectively compared clinical outcomes in patients with R/R FLT3-mutated AML in the CHRYSALIS and ADMIRAL trials who received prior midostaurin or sorafenib against those without prior FLT3 TKI exposure. Similarly high rates of composite complete remission (CRc) were observed in patients who received a FLT3 TKI before gilteritinib (CHRYSALIS, 42%; ADMIRAL, 52%) and those without prior FLT3 TKI therapy (CHRYSALIS, 43%; ADMIRAL, 55%). Among patients who received a prior FLT3 TKI in ADMIRAL, a higher CRc rate (52%) and trend toward longer median overall survival was observed in the gilteritinib arm versus the SC arm (CRc = 20%; overall survival, 5.1 months; HR = 0.602; 95% CI: 0.299, 1.210). Remission duration was shorter with prior FLT3 TKI exposure. These findings support gilteritinib for FLT3-mutated R/R AML after prior sorafenib or midostaurin.
Human C-terminal CUBN﻿﻿ variants associate with chronic proteinuria and normal renal function
Authors: Mathilda Bedin, Olivia Boyer, Aude Servais, Yong Li, Laure Villoing-Gaudé, Marie-Josephe Tête, Alexandra Cambier, Julien Hogan, Veronique Baudouin, Saoussen Krid, Albert Bensman, Florie Lammens, Ferielle Louillet, Bruno Ranchin, Cecile Vigneau, Iseline Bouteau, Corinne Isnard-Bagnis, Christoph J. Mache, Tobias Schäfer, Lars Pape, Markus Gödel, Tobias B. Huber, Marcus Benz, Günter Klaus, Matthias Hansen, Kay Latta, Olivier Gribouval, Vincent Morinière, Carole Tournant, Maik Grohmann, Elisa Kuhn, Timo Wagner, Christine Bole-Feysot, Fabienne Jabot-Hanin, Patrick Nitschké, Tarunveer S. Ahluwalia, Anna Köttgen, Christian Brix Folsted Andersen, Carsten Bergmann, Corinne Antignac, Matias Simons
Journal: Journal of Clinical Investigation (2022)
Recurrent Eye and Ear Pain in an Older Patient
Authors: Monica Yang, Mary Margaretten
Journal: JAMA (2022)

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Alterations in coronary resistance artery network geometry in diabetes and the role of Tenascin C
Authors: I Aykac
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: None. Background and Aims: Geometrical alterations in the coronary resistance artery network and potential involvement of the Tenascin C (TNC) protein were examined in diabetic mice. Methods Diabetes was induced by streptozotocin injections (n=7-11 animals in each group) in Wild type (A/J) and Tenascin C KO (TNC KO) mice, and 16-18 weeks later the heart was removed and the whole subsurface network of the left coronary artery was microprepared (down to branches of 40 µm outer diameter), in situ pressure-perfused and studied using video-microscopy. Outer and inner diameters, wall thicknesses and bifurcation angles were measured on whole network pictures reconstructed into collages at 1.7 µm pixel resolutions. Results Diabetic networks featured abnormal morphological alterations including trifurcations, sharp bends of larger branches, and branches directed in the retrograde direction (p&amp;lt;0.001 by the χ2 test). Networks of TNC KO mice tended to form early divisions producing parallel running larger branches (p&amp;lt;0.001 by the χ2 probe). Diabetic networks were substantially more abundant in 100-180 µm components, appearing in 2-5 mm flow distance from orifice. This was accompanied by thickening of the wall of larger arterioles (&amp;gt;220 µm) and thinning of the wall of a population of smaller (100-140 µm) arterioles (p&amp;lt;0.001). Interestingly, diabetes model by STZ-injection did not induce further geometrical changes in TNC KO mice. Blood flow should cover larger distances in diabetic networks. Conclusion In diabetic mice, a combined network remodelling of the coronary vasculature was observed with hypertrophic and hypotrophic remodelling and vasculogenesis at well defined, specific positions of the network. TNC plays an important role in the formation of network geometry, and TNC knockout induces parallel fragmentation preventing diabetes-induced abnormal vascular morphologies